A goal of this proposal is to understand mechanisms that occur prior to and following tau deposition within the forebrain of htau mice to help delineate cellular events that govern neurodegeneration within the human central nervous system. A goal is to assess pathological changes in gene expression within vulnerable populations while avoiding potential contamination from spared neuronal cell types and noneuronal populations. In the series of studies proposed herein, expression profile analysis of hippocampal CA1 pyramidal neurons, dentate gyrus granule cells, and layer ll/lll neocortical pyramidal neurons will be performed on hTau mice at several key time points during the lifespan, including pre-pathology (2 months of age), early pathology (6-8 months), moderate pathology (12 months), and severe pathology (16-17 months). The experimental design consists of microaspiration of identified neuronal populations via laser capture rnicrodissection followed by a novel single cell RNA amplification methodology developed in the laboratory of the Principal Investigator combined with custom-designed cDNA array analysis. This experimental design allows for simultaneous quantitative analysis of hundreds of transcripts from individual neurons. Aim 1 consists of a time course analysis within individual neuronal populations in hTau mice at the 4 defined time points. Aim 2 comprises a similar time course analysis on double transgenic htau/APP mice to assess single cell expression profiles in mice that accumulate both hallmark proteins seen in the Alzheimer's disease brain. Aim 3 consists of an experimental lesion paradigm (perforant path transection) to assess the effects of a central nervous system axotomy response in htau and htau/APP mice. These studies are hypothesized to elucidate early biomarkers for early cell-specific synaptic and neurodegenerative disorders.